The concept of a pre-clinical, drug screen for genetic effects was developed in Phase I of this project. The screen consists of inbred rats bred in a combinatorial fashion such that F1 offspring mimic the genetically diverse human population, while maintaining the phenotypic accuracy of an inbred strain. The combinatorial design enables "genome subtraction" strategies for ultimately localizing the gene(s) involved. By measuring clinical chemistry phenotypes and histology, Phase I studies showed that the combinatorial rat panel (termed the PharmaGenix Panel) can detect drug effects better than commonly used standard strains. For the 3 drugs tested, varied toxic responses were found in the different PharmaGenix rat lines establishing that either a genetic susceptibility or resistance exists for the drug treatment. In Phase II studies, PhysioGenix will validate that the PharmaGenix Panel has enhanced sensitivity and specificity as a pharmacogenetic sensor by screening drugs that have known toxic effects in kidney, liver, and heart. A second aim will be to relate the drug toxicity detected by PharmaGenix rats to those previously characterized by the pharmaceutical industry. Commercial launch of the PharmaGenix Panel in Phase III is intended to meet both the discovery and pre-clinical needs of the pharmaceutical industry.